Polycystic ovary syndrome (PCOS) is one of the most common conditions of young women, and it is frequently associated with insulin resistance, glucose intolerance and other features of the insulin resistance or metabolic syndrome (MBS). In addition, affected women have significantly elevated mean LDL levels and an increased prevalence of at risk LDL levels, independent of obesity. There is a genetic susceptibility to PCOS and we have identified a major susceptibility gene on chromosome 19p3.2 near the insulin receptor gene using the reproductive phenotype of hyperandrogenemia. We have now mapped the location of this variant (allele 8 [A8] D19S884) to an allele of a dinucleotide repeat in intron 55 of the fibrillin 3 gene. Our family studies indicate that: 1) both reproductive and metabolic abnormalities are heritable, 2) male as well as female first-degree relatives (FDRs) are affected, 3) hyperandrogenemia is an independent predictor of MBS and LDL elevations and 4) A8 is associated with a more severe metabolic phenotype in both probands and their FDRs. We have extremely exciting new data that A8 is associated with hepatic insulin resistance. The overarching hypothesis of this proposal is that 1) hyperandrogenemia plays an independent role in the pathogenesis of the metabolic abnormalities in PCOS, 2) hyperandrogenemia results from A8 PCOS susceptibility variant and 3) hyperandrogenemia begins early in life producing metabolic abnormalities prior to puberty. There are two specific aims. Aim 1: To test the hypothesis that there are premenarchal markers of PCOS that identifies girls at risk for metabolic abnormalities. FDRs will be studied to determine whether there is a premenarchal phenotype and whether A8 identifies at risk girls. Specific Aim 2: To test the hypothesis that hyperandrogenemia, alone or in synergy with insulin resistance, contributes to metabolic abnormalities in young women with PCOS. We will determine whether the androgen receptor antagonist flutamide, the insulin sensitizing agent metformin or a combination of these medications reduces visceral adiposity, improves insulin sensitivity, or ameliorates dyslipidemia in women with PCOS. Further, we will determine whether A8 genotype predicts response to these interventions. The proposed research has substantial scientific as well as public health implications because it promises to identify precursors of and novel therapeutic targets for metabolic abnormalities in PCOS. [unreadable] [unreadable] [unreadable]